1-100270678-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003729.4(RTCA):​c.412A>C​(p.Met138Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000558 in 1,613,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

RTCA
NM_003729.4 missense, splice_region

Scores

1
1
17
Splicing: ADA: 0.003430
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83
Variant links:
Genes affected
RTCA (HGNC:17981): (RNA 3'-terminal phosphate cyclase) This gene encodes a member of the RNA 3'-phosphate cyclase family. The encoded protein plays a role in RNA metabolism by catalyzing the ATP-dependent conversion of the 3'-phosphate of RNA substrates to a 2',3'-cyclic phosphodiester. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27769572).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RTCANM_003729.4 linkc.412A>C p.Met138Leu missense_variant, splice_region_variant Exon 4 of 11 ENST00000370128.9 NP_003720.1 O00442-1
RTCANM_001130841.2 linkc.451A>C p.Met151Leu missense_variant, splice_region_variant Exon 5 of 12 NP_001124313.1 O00442-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RTCAENST00000370128.9 linkc.412A>C p.Met138Leu missense_variant, splice_region_variant Exon 4 of 11 1 NM_003729.4 ENSP00000359146.4 O00442-1
RTCAENST00000260563.4 linkc.451A>C p.Met151Leu missense_variant, splice_region_variant Exon 5 of 12 1 ENSP00000260563.4 O00442-2
RTCAENST00000483474.1 linkn.622A>C splice_region_variant, non_coding_transcript_exon_variant Exon 5 of 6 3
RTCAENST00000498617.5 linkn.650A>C splice_region_variant, non_coding_transcript_exon_variant Exon 4 of 6 5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251002
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135650
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461264
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
726938
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.451A>C (p.M151L) alteration is located in exon 5 (coding exon 5) of the RTCA gene. This alteration results from a A to C substitution at nucleotide position 451, causing the methionine (M) at amino acid position 151 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
19
DANN
Benign
0.89
DEOGEN2
Benign
0.11
T;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.14
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.17
Sift
Benign
0.16
T;T
Sift4G
Benign
0.38
T;T
Polyphen
0.0060
B;B
Vest4
0.40
MutPred
0.55
Gain of catalytic residue at M138 (P = 0.0329);.;
MVP
0.30
MPC
0.10
ClinPred
0.19
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.28
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0034
dbscSNV1_RF
Benign
0.030
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752820408; hg19: chr1-100736234; API